Among diseases of circulatory organs, a pathologic condition characterized by insufficient blood flow from the ventricle to peripheral organs is called heart failure and classified into acute heart failure and chronic heart failure.
Acute heart failure is defined as a condition of cardiac dysfunction caused by rapid deterioration of the circulation dynamics. Common symptoms include marked dyspnea due to pulmonary congestion or cardiogenic shock due to low cardiac output, expectoration of foamy sputum, oliguria or anuria, cold extremities, lowering of blood pressure, cold sweat and tachycardia (sometimes bradycardia). Unless treated immediately, patients suffering from acute heart failure will soon die. On the other hand, chronic heart failure is an equilibrium state in which compensation mechanisms such as cardiac hypertrophy work because of slow progress of heart failure observed in old myocardial infarction and dilated cardiomyopathy; common symptoms include shortness of breath, fatigability, reduced exercise tolerance, enlargement of the liver and spleen, edema and varicosis of peripheral veins. Therefore, improving the prognosis of life is the ultimate goal of treatment of chronic heart failure and the goals of management are to improve exercise tolerance and the quality of life (QOL).
Thus, acute and chronic heart failures differ in pathological conditions and the object of treatment and it is important to choose the right therapeutic drugs specific to each type of heart failure. For patients with acute heart failure, saving their life is an ultimate goal, cardiotonic preparations are chosen as therapeutics that enhance the reduced myocardial contractility and which can improve the aggravated circulation dynamics. However, if cardiotonic preparations are administered to patients with chronic heart failure who are in stable condition, the already fatigued heart muscle is contracted more by added stimulation with the cardiotonic agent and the condition progresses adversely.
Therapeutics of acute heart failure developed so far are receptor stimulating drugs (e.g. dopamine) and phosphodiesterase (PDE) inhibitors (e.g. amrinone) but their vasodilating action precludes use in hypotensive patients.
Therefore, drugs for acute heart failure are desired that can be used in hypotensive and other patients for whom the application of conventional therapeutics for acute heart failure has not been indicated.
Also desired are pharmaceuticals applicable to the patient during a transition period from completion of treatment for acute heart failure to beginning of chronic heart failure, through which the state of the disease stabilizes slowly.
Reports have been made of the efficacy for heart disease of a growth hormone (hereunder abbreviated as GH), a GH releasing peptide (hereunder abbreviated as GHRP) or a GH secretagogue (hereunder abbreviated as GHS). Pharmacia & Upjohn (WO 9822124) evaluated the efficacy of hexarelin for heart failure in an rat isolated heart(for details, see Berti et al., Eur. J. Pharmacol. 334:201-207, 1997; J. Cardio. Pharmacol. 32:260-265, 1998; and Endocrinology 140:4024-4031, 1999). Eli-Lilly (WO 9908697) evaluated the therapeutic efficacy of GRP-2 (the same molecule as pralmorelin) for chronic heart failure, in particular, congestive heart failure, using rats with hereditary dilated cardiomyopathy.
However, none of these reports include data on the therapeutic efficacy for acute heart failure.
Deghenghi (U.S. Pat. No. 5,932,548) has reported that a specified peptide containing lysine in the sequence binds to the heart and increases its perfusion pressure. According to the more detailed report by Bodart et al. (Circ. Res. 85:796-802, 1999), GHRP elevates the perfusion pressure of the heart and GHRP reduces its contractility instead.
Hence, it has heretofore been unpredictable to use GHRP or GHS in the treatment of acute heart failure.
An object of the invention is to provide a preparation for preventing or treating heart failure that has cardiotonic action based on adequate increase in myocardial contractility and cardiac output. A further object of the invention is to provide a preparation for preventing or treating acute heart failure, chronic heart failure at a phase of acute exacerbation or heart failure at a phase of transition to chronic heart failure. Another object of the invention is to provide a preparation for preventing or treating heart failure that has no side effects including tachycardia, arrhythmia, an increased heart rate and hypotension, in spite of cardiotonic action. A still further object of the invention is to provide a drug for acute heart failure that can be applied to hypotensive and other patients for whom the application of conventional therapeutics for acute heart failure has not been indicated.